4 years ago

QRS/T-wave and calcium alternans in a type I diabetic mouse model for spontaneous postmyocardial infarction ventricular tachycardia: A mechanism for the antiarrhythmic effect of statins

The incidence of sudden arrhythmic death is markedly increased in diabetics. Objective The purpose of this study was to develop a mouse model for postmyocardial infarction (post-MI) ventricular tachycardia (VT) in the diabetic heart and determine the mechanism of an antiarrhythmic effect of statins. Methods ECG transmitters were implanted in wild-type (WT), placebo, and pravastatin-treated type I diabetic Akita mice. MIs were induced by coronary ligation, and Ca2+ transients were studied by optical mapping, and Ca2+ transients and sparks in left ventricular myocytes (VM) by the Ionoptix system and confocal microscopy. Results Burst pacing of Akita mouse hearts resulted in rate-related QRS/T-wave alternans, which was attenuated in pravastatin-treated mice. Post-MI Akita mice developed QRS/T-wave alternans and VT at 2820 ± 879 beats per mouse, which decreased to 343 ± 115 in pravastatin-treated mice (n = 13, P <.05). Optical mapping demonstrated pacing-induced VT originating in the peri-infarction zone and Ca2+ alternans, both attenuated in hearts of statin-treated mice. Akita VM displayed Ca2+ alternans, and triggered activity as well as increased Ca2+ transient decay time (Tau), Ca2+ sparks, and cytosolic Ca2+ and decreased SR Ca2+ stores all of which were in part reversed in cells from statin treated mice. Homogenates of Akita ventricles demonstrated decreased SERCA2a/PLB ratio and increased ratio of protein phosphatase (PP-1) to the PP-1 inhibitor PPI-1 which were reversed in homogenates of pravastatin-treated Akita mice. Conclusion Pravastatin decreased the incidence of post-MI VT and Ca2+ alternans in Akita mouse hearts in part by revering abnormalities of Ca2+ handling via the PP-1/PPI-1 pathway.

Publisher URL: www.sciencedirect.com/science

DOI: S1547527117306227

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